A clear dependence of structural biology on the crystallization of proteins, nucleic acids, viruses, and other macromolecular complexes has developed, as the vast majority of molecular models are now derived from X-ray crystallography. Crystal growth has come to play a crucial role in the entire enterprise of structure determination in the laboratories of both individual investigators, and in large structural genomics centers. The dependence is particularly acute with regard to the more intractable macromolecules such as membrane proteins and glycoproteins. Current approaches to macromolecular crystallization, while successful in perhaps 40% of cases, have not proven themselves able to successfully address many of the most biologically and medically significant problems. We propose to develop an alternate strategy for the crystallization of macromolecules that does not, like current methods, depend on the optimization of traditional variables such as pH and precipitant concentration, but is based on the hypothesis that many conventional small molecules might establish stabilizing, intermolecular, non covalent crosslinks in crystals, and thereby promote lattice formation. To test the hypothesis, we carried out preliminary experiments encompassing 18,240 crystallization trials using 81 different proteins, and 200 chemical compounds. Statistical analysis of the results demonstrates the validity of the idea. In addition, we have also conducted X-ray diffraction analyses of some of the crystals grown in the experiments. These clearly show incorporation of the conventional molecules into the protein crystal lattices, and they further validate the underlying hypothesis. We propose to extend the investigations to include a broader and more diverse set of proteins, including membrane proteins and macromolecular complexes, an expanded search of conventional and biologically active small molecules, and a wider range of precipitants. The strategy proposed here is essentially orthogonal to current approaches and has an objective of doubling the success rate of today. [unreadable] [unreadable] [unreadable]